A major theme of the next grant period will be the exploration of the chemistry of 2,5-cyclohexadien-1-ones. These versatile synthetic intermediates are constructed from readily available benzoic acid derivatives. The synthetic methodology that is developed from this investigation will be applied to the total synthesis of several medicinally and/or biologically important natural products. Enantioselective intramolecular cycloadditions to prochiral 2,5- cyclohexadien-1-ones will be explored. The aim is to direct regioselective addition to one double bond by the use of a chiral auxiliary attached to C(4). Specifically, the intramolecular photochemical 2+2 and 2+4 cycloadditions, the Diels-Alder cycloaddition, the 1,3-dipolar cycloaddition, the organocuprate conjugate addition-cyclization, and the reductive cyclization of suitably substituted prochiral 2,5-cyclohexadien-1-ones will be studied. The intramolecular 2+2 photocycloaddition will be applied to the first enantioselective total synthesis of the marine allomone 9-isocyanopupukeanane (59). Oxyallyl zwitterions will be generated by photorearrangement of 2,5-cyclohexadien-1-ones and these reactive intermediates will undergo intramolecular cycloadditions to olefins, dienes, and organic azides. Other intramolecular reactions of photogenerated oxyallyl zwitterions with alcohols, amines, carbonyl groups, phosphine imines, pyrroles, indoles, and pyridones hold promise for the preparation of a wide range of heterocyclic ring systems. The intramolecular 2+2 photocycloaddition of 4-butenyl-2,5- cyclohexadien-1-ones is to be used in an enantioselective construction of the cembrene-derived diterpenes kempane-2 (84a) and the kempane 84b. Another approach to the kempanes will utilize the lithium dimethylcuprate conjugate addition-cyclization of 4- substituted 2,5-cyclohexadien-1-ones. The first enantioselective total syntheses of selected lycorane alkaloids will be carried out. Lycorine (121) and related alkaloids exhibit antiviral, antineoplastic, and short-term hypotensive activity. Enantioselective total syntheses of the most highly prescribed analgesic agent morphine (129b) and the antitussive codeine (129a) also will be developed during the next grant period.